Nearly three quarters of women develop hot flashes during the menopausal transition, and up to a third report hot flashes that persist for more than a decade after menopause. While estrogen therapy is effective in suppressing hot flashes, it is associated with increased risk of endometrial cancer, and when combined with a progestin to prevent endometrial hyperplasia, it also increases risk of coronary disease, thromboembolic events, and breast cancer, particularly in women who are 5 or more years past menopause. As a result, there is widespread interest in identifying non-hormonal treatments for hot flashes that are both effective and safe. While prior efforts to identify non-hormonal treatments have focused on possible central triggering mechanisms, the final pathway underlying the physical manifestation of the hot flash is peripheral vasodilation. Clinical studies have shown that nitric oxide (NO) plays an important role in mediating vasodilation during hot flashes, with local cutaneous blockade of NO synthase suppressing hot flashes. One pharmacologic agent with direct and potent effects on NO-mediated vasodilation is nitroglycerin (NTG), an organic nitrate that is widely used to treat chest pain in patients with coronary disease. Initial use of NTG increases production of NO, promotes vascular smooth muscle relaxation, and triggers vasodilation; however, continued use of NTG rapidly leads to tolerance to both exogenous and endogenous nitrates, due to enhanced NO degradation. This tolerance offers a potentially innovative approach to treating hot flashes, as women who develop tolerance should experience a marked reduction in hot flash-related vasodilation. To explore the possibility of using NTG to treat menopausal hot flashes, our research team conducted a pilot trial of escalating-dose, uninterrupted transdermal NTG in 19 peri- and postmenopausal women with 7 or more hot flashes per day. All women were started on a generic 0.1 mg/hr NTG patch (applied daily without patch- free periods) and underwent dose escalation on a weekly basis to 0.4 or 0.6 mg/hr as tolerated. Over 4 weeks, the average frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P<0.01 for both). Women also demonstrated a 33% to 68% improvement in scores on insomnia, depression, and quality-of-life measures. To evaluate the efficacy, safety, and tolerability of this novel treatment strategy, we now propose to conduct a rigorous, randomized, double-blinded, placebo-controlled trial in 140 peri- or postmenopausal women. Women who document frequent hot flashes and who do not have coronary disease or contraindications to NTG therapy will be randomly assigned to uninterrupted use of transdermal NTG or identical-appearing placebo patches for 24 weeks. By providing the first rigorous evidence of the efficacy and safety of NTG for hot flashes, this research may help decrease the burden of the most common symptomatic complaint of menopausal women.